Colon cancer is a major health concern of the United States, with an estimated 129,400 new cases reported in 1999. Colon cancer is now the second leading cancer killer of both men and women in the U.S. after lung cancer. The successful management of this disease will require the discovery of safe and effective pharmacological agents. The goal of the present proposal is to validate HMGI-C (High Mobility Group I-C), an architectural transcription factor which regulates gene expression in tumorigenesis, as a drug target for colon cancer. The experimental approach will involve the inactivation of HMGI-C in Min mice, a widely accepted model of colon cancer resulting from an ethylnitrosurea (ENU) induced nonsense mutation at codon 850 of the murine Apc (adenomatous polyposis coli) gene. Germline mutations in humans in the APC gene are responsible for familial adenomatous polyposis, an inherited form of colon cancer. APC gene defects are also highly prevalent in sporadic colon tumors. It is hoped that inactivation of HMGI-C will attenuate colon cancer by inhibiting tumor formation or progression, thus validating HMGI-C as a drug target for colon cancer and setting the stage for a Phase II investigation into possible drug discovery. PROPOSED COMMERCIAL APPLICATION: Successful completion of this project would open up new prospects for the discovery of effective, clinically valuable drugs for the treatment of colon cancer which would have an enormous commercial potential. It is now estimated that in the United States alone, 129,400 new cases of colon cancer were reported, indicating the demand for safe, reliable pharmaceuticals.